Voltage dependent sodium (NaV1) and in some cases low voltage activated calcium (CaV3) channels are membrane proteins that in all excitable cells including neurons, lay in the basis of action potential generation and propagation Inhibition of NaV1 channels causes a neuron to be incapable of firing action potentials and therefore incapable of encoding and transmitting information.
Neuropathic pain is a compound neuronal process involving both peripheral hyperexcitability and central sensitization. Peripheral hyperexcitability could be due to ectopic spontaneous firing of damaged dorsal root ganglion (DRG) neurons which is transmitted to the central nervous system (CNS) and sensed as pain. Tackling this phenomenon by specifically inhibiting NaV1 (or CaV3) channels in damaged sensory nociceptive neurons in the periphery may be effective in reducing or eliminating neuropathic pain. This could be achieved by either local application of non-specific Nav blockers (such as local anesthetics) or by systemic application of NaV1 blockers, which specifically recognize NaV1 channels in DRG neuron membranes. One generic approach to increase this specificity is by avoiding the CNS (in which most NaV1 isoforms are crucial for neuronal activity). The other approach is to find selective blockers to NaV1 isoforms, which expression is restricted to hyperexcitable DRG neurons (Devor, 2006; Cummins et al. 2007). One of the main issues regarding NaV1 blockers specificity is avoidance of cardiac blockade activity.
The Tetrodotoxin (TTX)-sensitive, NaV1.3, channel is normally expressed in the CNS and the peripheral nervous system (PNS) during the embryonic stage and its expression is heavily down regulated with maturation. However, up-regulation of the channel expression is reported following neuronal injury. These observations, suggest that specifically targeting NaV1.3 isoforms, could block exclusively damaged-hyperexcitable DRG neurons (Devor, 2006; Cummins et al. 2007).
The TTX-resistant, NaV1.8 channel is expressed almost exclusively in the PNS and has been shown to mediate most of the well documented TTX resistant component of DRG neurons action potentials. Recently, a paper has been published, emphasizing the importance of NaV1.8 channels as a target in pain control (Jarvis, M. F., et al. 2007; Zimmermann, K., et al. 2007).
The importance of treating pain, by targeting a protein which is expressed specifically in the periphery is highlighted by the case of ASIC1 channels which are expressed in the spinal cord and their inhibition induces analgesia in a rat model of neuropathic pain. However, administration of the peptide modulator, should be direct as in systemic administration the peptides do not cross the blood brain barrier to reach their target protein (Mazzuca, M., et al. 2007, Nat. Neurosci. 10, 943).
Throughout this specification, various scientific publications and patents or published patent applications are referenced. The disclosure of all these publications in their entireties is hereby incorporated by reference into this specification in order to more fully describe the state of the art to which this invention pertains. Citation or identification of any reference in this section or any other part of this application shall not be construed as an admission that such reference is available as prior art to the invention.